Phospholipase C-δ1 Is a Critical Target for Tumor Necrosis Factor Receptor–Mediated Protection against Adriamycin-Induced Cardiac Injury

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-04, Vol.66 (8), p.4329-4338
• Main Authors: Lien, Yu-Chin, Noel, Teresa, Liu, Hua, Stromberg, Arnold J., Chen, Kuey-Chu, St. Clair, Daret K.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-3424

The clinical application of adriamycin, an exceptionally good chemotherapeutic agent, is limited by its dose-related cardiomyopathy. Our recent study showed that tumor necrosis factor-α (TNF-α) receptors mediated cytoprotective signaling against adriamycin-induced mitochondrial injury and cardiomyocyte apoptosis. In the present study, we investigated the potential targets of TNF receptor–mediated cytoprotective signaling by global genome microarray analysis using wild-type and TNF receptor–deficient mice. Microarray analysis revealed that adriamycin treatment induced the down-regulation of several mitochondrial functions and energy production–related genes in double TNF receptor–deficient mice, notably, phospholipase C-δ1, a protein involved in fatty acid metabolism and calcium regulation. The role of phospholipase C-δ1 in TNF receptor–mediated cardioprotection against adriamycin-induced injury was evaluated by measuring changes in cardiac function using high-frequency ultrasound biomicroscopy. Selective inhibition of phospholipase C activity in wild-type mice by its inhibitor, U73122, exacerbated adriamycin-induced cardiac dysfunction. Inhibition of phospholipase C-δ1 resulted in the significant decrease of left ventricular ejection fraction and fractional shortening, and the decreased levels were similar to those observed in adriamycin-treated double TNF receptor–deficient mice. The data derived from the global genome analysis identified phospholipase C-δ1 as an important target for TNF receptors and revealed the critical role of TNF receptor signaling in the protection against adriamycin-induced cardiotoxicity. (Cancer Res 2006; 66(8): 4329-38)